Cervical cancer is the leading cause of cancer mortality for women in the developing world, where 80% of cases occur, and it remains a significant health problem in parts of the United States (U.S.) like Appalachia, the Texas/Mexico border, and the inner cities. The introduction of the Papanicolaou smear and organized screening programs have decreased both the incidence and mortality of cervical cancer in every country where established. The infrastructure needed to maintain these screening programs is both large and expensive. Despite its enormous success, the Papanicolaou smear has a sensitivity of 60% and specificity of 90%. Our group is assessing emerging technologies in both the developed and developing world. Our goal is to improve the screening and detection of cervical cancer and its precursors using optical technologies and molecular imaging. We have focused on decreasing health care costs and patient anxiety in the developed world and in the creation of devices that automate detection and reduce infrastructure in the developing world. The introduction of HPV vaccines may reduce the incidence of cervical cancer in North America over the next twenty years. There is much left to study about the effectiveness, duration, and administration of the vaccine. Visual Inspection with Acetic Acid, or VIA, has been introduced as replacement for the Papanicolaou smear in low resource settings. VIA involves the use of vinegar on the cervix in order to identify keratinized lesions. While VIA has the enormous advantage of being performed in real-time, it is difficult to quality-assure. In Project 3, we will conduct five clinical trials: training and validation of a classification algorithm for a multispectral digital colposcope (MDC) in 677 patients, examination of the interaction of a spectroscopic point probe and the MDC in order to derive a combined algorithm for this two-par device in 128 patients, a pilot study of a battery-powered and low-cost diagnostic imaging aid (DIA) in 60 patients, a pilot study of an in vivo confocal microscope in 60 patients, and a pilot study of a contrast agent (determined to be optimal by a trial in Project 1) in 60 patients. In order to optimize the trials, only patients with known high-grade cervical lesions are being recruited at five clinical sites: the British Columbia Cancer Agency, M.D. Anderson Cancer Center, Lyndon Baines Johnson County Hospital, Ben Taub General Hospital, and the Baylor College of Medicine.